Changes in cardiac structure and function from 3 to 12 months after hospitalization for COVID‐19

Abstract Background Cardiac function may be impaired during and early after hospitalization for COVID‐19, but little is known about the progression of cardiac dysfunction and the association with postacute COVID syndrome (PACS). Methods In a multicenter prospective cohort study, patients who had been hospitalized with COVID‐19 were enrolled and comprehensive echocardiography was performed 3 and 12 months after discharge. Twenty‐four‐hour electrocardiogram (ECG) was performed at 3 and 12 months in patients with arrhythmias at 3 months. Results In total, 182 participants attended the 3 and 12 months visits (age 58 ± 14 years, 59% male, body mass index 28.2 ± 4.2 kg/m2). Of these, 35 (20%) had severe COVID‐19 (treatment in the intensive care unit) and 74 (52%) had self‐reported dyspnea at 3 months. From 3 to 12 months there were no significant overall changes in any measures of left or right ventricle (LV; RV) structure and function (p > .05 for all), including RV strain (from 26.2 ± 3.9% to 26.5 ± 3.1%, p = .29) and LV global longitudinal strain (from 19.2 ± 2.3% to 19.3 ± 2.3%, p = .64). Changes in echocardiographic parameters from 3 to 12 months did not differ by COVID‐19 severity or by the presence of persistent dyspnea (p > .05 for all). Among patients with arrhythmia at 3 months, there was no significant change in arrhythmia burden to 12 months. Conclusion Following COVID‐19, cardiac structure and function remained unchanged from 3 to 12 months after the index hospitalization, irrespective of COVID‐19 severity and presence of persistent dyspnea. These results suggest that progression of cardiac dysfunction after COVID‐19 is rare and unlikely to play an important role in PACS.


| INTRODUCTION
Cardiac injury, defined by elevated levels of cardiac troponin (cTn) is common in patients hospitalized with COVID-19 1 and is associated with severe illness and in-hospital death. [2][3][4] Studies assessing cardiac function by echocardiography in hospitalized patients with COVID-19 have demonstrated impairments in right ventricular (RV) function [5][6][7][8] and to a lesser extent left ventricular (LV) dysfunction. 6 The presence of cardiac dysfunction in the acute phase of COVID-19 is associated with worse short-term outcomes. 6,9,10 In the early convalescent phase, studies have reported inconsistent findings depending on the imaging modality used, the severity of COVID-19, and the time from the acute infection. Studies using cardiac magnetic resonance (CMR) imaging have suggested that a high proportion of patients have a myocardial scar and diffuse fibrosis, 11 while others report substantially lower prevalence. 12 However, the presence of structural and functional cardiac abnormalities in the early convalescent phase varies between echocardiographic studies. A high prevalence of diastolic dysfunction and prevailing reduced RV function but sustained LV function has been shown, [13][14][15] while others have found little pathology by echocardiography approximately 3 months after hospitalization. 16,17 Cardiac arrhythmias during acute COVID-19 have been reported, 18 while the prevalence and progression of cardiac arrhythmias in the convalescent phase have not been extensively studied.
Although short-term alterations in cardiac structure and function after COVID- 19 have been described, no study has evaluated longitudinal changes in cardiac structure and function during the first year after hospitalization for COVID- 19. We hypothesized that there would be no significant changes in cardiac structure or function or arrhythmic events from 3 to 12 months after COVID-19. In this multicenter prospective cohort follow-up study of patients hospitalized with COVID-19, we aimed to assess the prevalence of cardiac dysfunction and arrhythmias 12 months after the acute infection, the changes in echocardiographic parameters, and arrhythmic events from 3 to 12 months, according to the severity of the  infection and presence of post-COVID-19 dyspnea.

| Assessment of dyspnea
Dyspnea was classified by the modified Medical Research Council (mMRC) dyspnea scale at the 3 and 12-month visits. mMRC is a selfrating tool to measure the degree of disability that breathlessness poses on day-to-day activities on a scale from 0 (no dyspnea) to 4 (maximum dyspnea). 22 Dyspnea was defined as mMRC ≥ 1 at the 3-month visit.

| Grading of severity
To compare patients based on severity of COVID-19, we classified patients based on: (1) need for intensive care unit (ICU) treatment compared to medical ward only; (2) respiratory criteria on admission to classify patients as "severe respiratory state" (either without Spo 2 < 90% without oxygen, SpO 2 < 95% with oxygen, requiring >3 L O 2 to maintain SpO 2 > 95% or respiratory rate > 30/min); (3) peak levels of CRP during the hospitalization to classify patients as "severe inflammatory state" (above the median value).

| Statistical methods
The baseline characteristics are presented as mean ± standard deviation or medians (1st to 3rd quartile, Q1−Q3) for continuous variables and as absolute numbers and percentages for categorical variables.
Delta values for change in echocardiographic variables from 3 to 12 months were generated by subtraction of the first value from the last value. All echocardiographic delta variables were assessed for normal distribution by histograms, Q−Q plots and the Shapiro−Wilk test.
Measurements at the 12-month visit were compared with the 3-month measurements by paired sample t-tests, and one sample t-tests for delta values to assess the difference from no change. Nonnormally distributed variables were also tested with the Wilcoxon matched-pairs signed-rank test. The proportion of patients with LV hypertrophy, LV systolic and diastolic dysfunction, elevated filling pressures, reduced RV function and RV dilatation at 3 months and 12 months were compared by the McNemar's paired proportions test. To assess individual changes from 3 to 12 months we investigated the proportion of patients with a 15% increase or decrease in LV function (LV GLS and LVEF) and RV function (RVLS and TAPSE), by model of longitudinal studies in cardiooncology, 23 and compared this with the McNemar's test. We also report 10% and 20% changes.

Changes in echocardiographic parameters between patients
with versus without treatment in the ICU, and between patients with versus without dyspnea at 3 months, were analyzed using multivariable linear regression. To adjust for possible confounders, we included the following a priori selected covariates in all models: age, sex, systolic blood pressure, heart rate, body mass index, and established cardiovascular disease, in addition to the baseline echocardiographic value for each measure (3-month visit).
All statistical analyses were performed using Stata Software (version 16; Stata Corp.).

| Patient characteristics
Of the 264 patients included in the PROLUN study, 200 patients had available echocardiograms at the 3-month visit, and among these 178 (89%) also attended the 12-month visit (Supporting Information: - Figure 1). Patients with both 3-and 12-month echocardiograms available were included in this study, and these patients had comparable baseline characteristics to the remaining PROLUN participants (Supporting Information: Table 1 3.1.1 | Cardiac structure and function 3 and 12 months after COVID-19 The mean values of LV structure, LV systolic function, LV diastolic function, RV structure, and RV function were within the guidelinerecommended limits of normal at both the 3-and 12-month visit (  Table 2).
When assessing changes in measurements of LV and RV function by 15% improvement or deterioration from 3 to 12 months, we found that 5 patients had deterioration and 6 patients had an improvement in LVGLS (p = .76) ( inflammatory state during COVD-19, there were no significant differences in changes in echocardiographic measurements between 3 and 12 months (Supporting Information: Table 5).

| Changes in cardiac structure and function by persistent dyspnea after COVID-19
At the 3-month visit, 74 (52%) of 142 with available data reported persistent dyspnea. At the 12-month visit, 84 (51%) reported persistent dyspnea (98% of those with dyspnea at 3 months). There were no consistent significant differences in echocardiographic variables by dyspnea at the 3 or 12-month visit, except for a tendency for smaller LVEDVi in patients with dyspnea at 12 months (Supporting Information: Table 6&7). There were no significant differences in changes in cardiac structure and function between patients with dyspnea at 3 months compared to those without dyspnea (p > .05 for all;Supporting Information: Table 8; Figure 2). The lack of association between changes in echocardiographic variables with dyspnea persisted in adjusted models (adjusted p > .05 for all).

| Changes in 24-h ECG detected arrhythmias after COVID-19
Among patients with arrhythmia at the 3 months visit (n = 40), there was a nonsignificant decrease in the proportion of patients with >10% PVCs from 3 to 12 months (n = 30 and n = 21, p = .32) and nonsustained ventricular tachycardia (NSVTs) (n = 8 and n = 1, p = .35; Supporting Information: Table 9). Patients with arrhythmia at 3 months had similar COVID-19 severity and prevalence of symptoms as those without arrhythmia. Two patients had >1 episode of NSVT at either the 3 or 12-month visit and both patients had severely reduced LV function with LVEF < 30%.

| DISCUSSION
In this multicenter study we assessed changes in cardiac structure recovery of the RV is still ongoing after 3 months in some patients.
This extends previous findings demonstrating improved RVLS from hospitalization for COVID-19 to 3 months follow-up. 13 However, as the overall change in RVLS to 12 months was nonsignificant, these findings must be viewed as hypothesis-generating.
Abnormalities in cardiac structure and function after COVID-19 have also been investigated with the use of CMR. In these studies, the prevalence of cardiac pathology after COVID-19 varies from 3% to 78%. 11,12,30 Findings reflective of diffuse fibrosis, myocardial edema, and myocardial scar have been reported, but the clinical and prognostic impact of these findings in the absence of cardiac dysfunction is unknown. A longitudinal CMR study reported almost normalization of cardiac findings from 3 to 6 months 31 Postacute COVID-19 (PACS) is defined as persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of COVID-19. 32 We found limited evidence of an association between changes in cardiac structure and function and persistent dyspnea. Increasing numbers of patients report long-term complications and dyspnea beyond what is expected after hospitalization with COVID-19 (i.e., PACS). 33 In our study, 52% and 51% reported dyspnea at 3 and 12 months, respectively. Studies done in the early convalescent phase do not find any correlation between symptoms and echocardiographic findings. 13,14,17,27 Our study extends these findings, as we do not find an association between symptoms and changes in echocardiographic parameters between 3 and 12 months post-COVID. There is no established pathophysiologic explanation for the persistent symptoms after COVID-19, and our findings suggest that long-term cardiac deterioration is unlikely to play a central role. Data from cardiopulmonary exercise testing post COVID-19 hospitalization suggest that obesity, deconditioning, dysautonomia, and lower ventilatory efficiency may be factors that contributes to the pathophysiologic mechanisms of dyspnea in PACS. 34,35 There has also been shown a circulatory impairment, 35 which may represent changes in pulmonary perfusion rather than cardiac dysfunction. (67%) had an available echocardiogram at the 3-month visit, and among these, 178 (89%) also had an available echocardiogram at the 12-month visit (Supporting Information: Figure 1). Although this is likely to introduce selection bias towards a healthier study population, we demonstrate comparable baseline characteristics to participants who were not part of this substudy (Supporting Information: Table 1).
This study used echocardiography to assess cardiac structure and function, which is less sensitive than CMR. However, we performed more sensitive echocardiographic measurements such as myocardial strain to improve the ability to detect subtle changes. The external validity of our study to current post-COVID-19 care may be limited by the fact that our population was enrolled at an early stage of the pandemic with different SARS-CoV-2 variants and therapeutic options than today. Furthermore, Norway was mildly affected by the pandemic compared to most other countries. Therefore, the threshold for ICU treatment may have been lower than in other places. Some patients did not have available measures of all echocardiographic parameters due to image quality (i.e., 21% had missing GLS, which is better than most population-based studies). We did not impute these variables as we investigated each echocardiographic parameter separately, and because these were the main outcome measures in the study. Due to limited capacity, only the participants with pathology at 3 months had a 24-h ECG examination at 12 months, which introduces substantial bias. Despite multiple testing we did not adjust the p value as this did not have an impact on our overall neutral results.

| CONCLUSIONS
Cardiac structure and function remained unchanged from 3 to 12 months after the index hospitalization for COVID-19, irrespective of initial COVID-19 severity. We found no association between changes in cardiac structure and function and the presence of persistent dyspnea, suggesting that these symptoms are not related to cardiac pathology from COVID-19. There was no significant change in arrhythmic burden among patients with documented arrhythmia at 3 months. In sum, our results suggest that progression of cardiac dysfunction after COVID-19 is rare and unlikely to play an important role in PACS.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.